rs121908318

chr8-142742343-A-Gchr8-142742343-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP5_Moderate

The NM_020427.3(SLURP1):c.43T>C(p.Trp15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,612,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: SLURP1 NM_020427.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.100

Genes affected

SLURP1 (HGNC:18746): (secreted LY6/PLAUR domain containing 1) The protein encoded by this gene is a member of the Ly6/uPAR family but lacks a GPI-anchoring signal sequence. It is thought that this secreted protein contains antitumor activity. Mutations in this gene have been associated with Mal de Meleda, a rare autosomal recessive skin disorder. This gene maps to the same chromosomal region as several members of the Ly6/uPAR family of glycoprotein receptors. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP5: Variant 8-142742343-A-G is Pathogenic according to our data. Variant chr8-142742343-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 4605.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-142742343-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLURP1	NM_020427.3	c.43T>C	p.Trp15Arg	missense_variant	1/3	ENST00000246515.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLURP1	ENST00000246515.2	c.43T>C	p.Trp15Arg	missense_variant	1/3	1	NM_020427.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000802 AC: 20 AN: 249320 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135440

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1460608 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 726594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74376

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Acroerythrokeratoderma Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 29, 2018	The p.Trp15Arg variant in SLURP1 has been reported 13 homozygous and 3 compound heterozygous individuals with clinical features of Mal de Meleda and segregated with disease in 9 affected releatives from at least 2 families (Eckl 2003, Nelle n 2013, Zhao 2014). This variant has been identified in 19/125816 European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org) and has been reported in ClinVar (Variation ID 4605). In vitro functional s tudies provide some evidence that the p.Trp15Arg variant may impact protein func tion (Favre 2007). In summary, this variant meets criteria to be classified as p athogenic for autosomal recessive Mal de Meleda based upon segregation studies a nd functional evidence. ACMG/AMP criteria applied: PM3_Strong, PP1_Strong, PS3_S upporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	0.0033	T
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	16
Dann	Benign	0.79
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.0000054	A
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.56
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Polyphen		0.81	P
Vest4		0.39
MutPred		0.85		Gain of methylation at W15 (P = 0.0101);
MVP		0.49
MPC		0.63
ClinPred		0.043	T
GERP RS		0.80
Varity_R		0.19
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908318; hg19: chr8-143823761;